PROJECT SUMMARY Most anti-cancer therapies designate cell death as the ultimate end goal. Yet, the fascinating biology beyond cell death is emerging as an important contributor to therapeutic outcome. A clinically-relevant example is immunogenic cell death (ICD)?characterized by its functional capacity to potentiate antitumoral T cell immunity. The current defining molecular hallmark of ICD is the release of damage-associated molecular patterns (DAMPs), which function as ?danger? signals to ultimately activate T cell immunity. However, our preliminary findings revealed that successful DAMP release alone was insufficient to promote ICD; leading us to challenge this dogma and reason that additional regulatory component(s), other than DAMPs, influence the immunogenicity of cell death. Herein, our new findings also revealed that an inhibitory DAMP (iDAMP) with unclear upstream regulatory mechanisms was concurrently released by dying cells as a physiologic response to chemotherapeutic treatment. Intriguingly, the pharmacological intervention to preclude iDAMP release by dying cells relieved the immunosuppressive constraints imposed by the iDAMP, and readily enabled a non-immunogenic chemotherapy to elicit an antitumoral T cell response. We now propose to elucidate 1) the unexplored upstream regulatory mechanism(s) of the iDAMP and 2) iDAMP blockade as a generalizable strategy to augment antitumoral T cell immunity. Our underlying hypothesis is that pharmacological intervention of the iDAMP axis poses as a paradigm-shifting approach to augment antitumoral T cell immunity and therapeutic efficacy. Knowledge gained from the proposed research will elucidate the upstream mechanism in epithelial cancer cells that regulates iDAMP biosynthesis and release as a physiologic response to anti-cancer therapy, as well as evaluate a therapeutic approach that can alleviate the immunosuppressive constraints of the iDAMP to augment antitumoral T cell immunity. The success of the proposed research will yield a compelling scientific rationale to move the field forward by translating our preclinical findings into clinical application.